1. Field of the Invention
The invention is related to the field of Nuclear Magnetic Resonance (NMR) and Magnetic Resonance Imaging (MRI) apparatus and methods. More specifically, the invention relates to methods and apparatus for using NMR for rapid, in-vivo determination of bone properties, such as Bone Mineral Density (BMD). The invention more particularly relates to NMR methods and apparatus for diagnosing diseases that affect bone, such as osteoporosis. In addition, the invention relates to methods and techniques of monitoring bone condition during progress of the disease, including the effect of different types of treatments on the disease.
2. Description of the Related Art
The description of the invention and its background are approached in the context of osteoporosis because osteoporosis is recognized as a significant public health problem, and NMR as well as other diagnostic techniques for bone studies have been widely applied and investigated. It is to be explicitly understood that the invention is not limited to the field of study, analysis and monitoring of osteoporosis.
a. Bone in a Human Skeleton
The skeleton serves to support the body, anchor muscles and protect vital organs. The human skeleton consists of approximately 80% of cortical (compact) bone and approximately 20% of trabecular (cancellous, or "spongy") bone. The structure and composition of individual bones varies, and is generally related to the specific function performed by the particular bone. Generally, an anatomical bone consists of about 25% by volume of a specific bone tissue and about 75% by volume of bone marrow. Bone marrow consists of yellow and red bone marrow. Yellow bone marrow includes primarily fat cells (about 85% by volume), water (about 15% by volume) and a small fraction of protein (typically less than about 1% by volume). Red bone marrow mainly includes erythropoetic tissue elements, and its composition is approximately 40% water by volume, 40% fat by volume, and 20% protein by volume. The overall mass of red marrow typically decreases with age. The lost red marrow mass is replaced with yellow marrow. At any age, the proportion of red and yellow marrow varies with the skeletal site. Of the specific bone tissue weight in any particular bone, only about 20% is organic matter (mainly collagen), about 70% is mineralized phase (crystals of hydroxyapatite and amorphous calcium phosphate) and about 10% is water.
In the foregoing discussion and in the description of the invention to follow, these definitions will be used. An "anatomical bone" is a structural, functional part of the skeleton such as the tibia, the radius, the calcaneus, for example. The term "bone" in general refers to a part of any of the previously mentioned anatomical bones, including cross-sections of any anatomical bone. "Bone tissue" is the tissue composition of the cortical bone and trabecular bone making up any anatomical bone. "Specific bone tissue" represents the part of bone tissue excluding any microscopic cavities, blood vessels and the like. The microscopic cavities include osteocytes, lacunae, canliculae, Haversian canals, and Volkmann's canals. "Bone matrix" is the specific bone tissue excluding any chemically bound water. The bound water is also known in the literature as the hydration shell. Bone matrix consists of organic matter, 95 percent of which is in the form of collagen fibers, and inorganic matter referred to as bone mineral. The foregoing definitions have been provided to clarity of the description to follow, because reconciliation of the various terminologies for bones and their components has been difficult since no techniques have been developed to measure the bone matrix quantity in vivo.
Bone continuously undergoes remodeling or turnover during a person's life. Older bone tissue is replaced at anatomically discrete sites with newly formed tissue to avoid cumulative skeletal fatigue damage. Approximately 20% of bone tissue is replaced annually by this process, on a cyclical basis throughout the skeleton. There are five phases to bone remodeling: activation, resorption, reversal, formation and quiescence. The entire remodeling process occurs over approximately 4 to 8 months, with a range of 3 months to 2 years depending on the particular bone.
In bone growth, and during the remodeling process in a normal, healthy person, the organic matter remains a relatively constant fraction of the total specific bone tissue volume, while mineralization of bone occurs by replacement of water by the previously described mineral phase (crystals of bone mineral). Mineralization and crystal growth continue until there is no space left for further mineral expansion. Crystals form and grow within a fixed volume by displacement of water. The space between the crystals become smaller and smaller as the crystals grow, until eventually a state of maximum mineralization is achieved. For bone crystals to grow, mineral ions must diffuse in from fluid circulation. As the intercrystalline spaces become so small as to approach atomic dimensions, ions can no longer diffuse at appreciable rates. Specifically, polyvalent ions of calcium, which form a large part of bone mineral, are large and have high electric charge that prevents them, by electric repulsion, from entering narrow intercrystalline spaces. The same size spaces, however are accessible to univalent ions. Additional chemical evidence suggests that the water in calcified tissues is largely in chemically bound form.
b. Osteoporosis
Osteoporosis is a systematic skeletal disease characterized generally by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in susceptibility to fracture. More specifically, in osteoporosis, the volume of the anatomical bones remains unchanged during progress of the disease, but the bones show cortical thickening and porosis, and the bones exhibit a specific bone tissue fraction and a bone mineral fraction of their total volumes which are less than the normal proportions of the anatomical bone volume. However, within the specific bone tissue, the ratio of mineral to organic matter and water remains relatively unchanged. The structural and chemical composition of the specific bone tissue in osteoporotic bone tissue is thus indistinguishable from that of normal bone. This has made analysis of osteoporotic bone difficult using methods known in the art for analyzing bone.
c. Radiologic Bone Densitometry
The National Osteoporosis Foundation has issued specific and aggressive recommendations for managing and preventing osteoporosis in, First guidelines for osteoporosis issues by National Osteoporosis Foundation in collaboration with multidisciplinary physician organizations (news release Nov. 5, 1998). These guidelines include the use of BMD as the single most reliable tool for assessing bone strength and osteoporosis risk. The rationale for using BMD as a monitoring and predictive tool is that there is a well-established relationship between BMD and the ability of bone to withstand compressive, torsional and bending forces. A strong correlation between BMD and the load necessary to induce skeletal failure has been shown, for example, by Johnston and Melton, Bone densitometry measurement and the management of osteoporosis, Primer on Metabolic Bone Diseases and Disorders of Mineral Metabolism, American Society for Bone and Mineral Research, Society Office, pp. 93-100 (1996). In-vivo radiologic bone densitometry methods for diagnosis and therapeutic follow-up include:
I. Conventional skeletal radiography.
This method is relatively insensitive and bone loss is apparent only when bone mass has decreased by about 30-50%.
II. Radiographic photodensitometry.
This method uses exposure to X-rays of a reference wedge alongside the area of interest in measuring the optical density of X-ray films of the bones in the area of interest.
III. Radiogrammetry.
This method relies on an expected linearity of measurements of X-ray films made of cortical bone taken under standardized conditions. The radiogrammetry technique gives values for the cortical width of bone, from which the cortical area of the bone can be derived. This technique is accurate in predicting bone ash weight, but is less sensitive and less specific than absorptiometric measurements, because it does not account for trabecular bone density or cortical bone porosity.
IV. Single Photon Absorptiometry (SPA).
This technique includes measurements related to attenuation by bone and soft tissue of a well-collimated gamma-ray beam. To account for soft tissue absorption, the body part being examined is immersed in a water bath that simulates a uniform soft tissue thickness. Single energy X-ray absorptiometry (SXA) is a related and newly developed technique suitable for scanning appendicular sites. It avoids the need for using specific radioisotopes.
V. Dual-energy Photon Absorptiometry (DPA).
This technique has to be used, for example, to analyze proximal femur and vertebral bodies, which are very irregular bones. The irregularity make delineation of the bones difficult. Furthermore, these bones are surrounded by a widely varying amount of fat, muscle mass and, in the case of the spine, is surrounded by gastrointestinal organs which may be partially filled with gas. These factors limit the use of SPA and SXA. The different thickness of soft tissue can be accommodated by simultaneous measurement of the transmission of gamma ray of two different energies.
VI. Dual-energy X-ray Absorptiometry (DXA).
DXA has now largely replaced DPA because of its greater precision, ease of use and freedom from several technical artifacts. There is no evidence to suggest that DXA has any disadvantages compared with DPA. The theory underlying DPA and DXA requires that there are only two energy absorptive components present, bone and soft tissue, each having uniform composition. In practice, fat has an additional component with attenuation characteristics that differ from those water, muscle and most organs. Fat is distributed non-uniformly in the region of the lumbar spine and may cause errors of up to 10% in estimation of spinal bone mineral mass. Errors can also be introduced by the presence of fat within the vertebral bone marrow.
VII. Quantitative Computed Tomography (OCT).
Under appropriate conditions QCT may provide a measure of volumetric bone mineral density, and cancellous bone can be measured independently of the surrounding cortical bone. The biggest source of error in single X-ray QCT systems is the fat within the bone marrow. Accuracy errors of up to 30% may be introduced from the presence of fat in marrow. The accuracy of QCT may be improved by performing scans at two different X-ray energy levels. Errors of in vivo measurement are much higher than those made in vitro, but the precision of dual-energy QCT can be as high as 10%, much higher than the 2% obtainable with single-energy QCT. A wide range of radiation doses has been used to perform QCT, with values as high as 40 mGy for dual-energy measurement. This comparatively high radiation dose limits the number of repeated measurements that can be done to a single patient, for example, to monitor progression of osteoporosis.
VIII. Photon-scattering Methods and Neutron Activation Analysis.
These techniques have been conceptually and experimentally developed for bone mineral density measurement. However, these techniques were not adequately assessed for screening.
IX. Ultrasound.
Evaluation of bone by ultrasound is based on measurement of velocity, attenuation or reflection of ultrasonic energy imparted to the bone. Interest in these techniques is based on the fact that ultrasonic energy does not introduce ionizing radiation to the body, and may provide some information concerning the structural organization of the bone in addition to information concerning bone mass or density. Ultrasound attenuation measurement has not yet been proven for use as a screening tool. Ultrasound reflection measurement may provide some indication of the material properties of bone but has not been widely studied. Speed of sound has been shown to be a function of both the mass and the modulus of elasticity of the bone, but there have been no studies as yet examining whether or not the speed of sound provides a measure of bone "quality" and a better assessment of bone fragility than bone densitometry alone.
d. Magnetic Resonance Imaging. Particularly of Human Bone
Magnetic Resonance Imaging (MRI) instruments can be used for determining structural properties of a bone. Methods of using MRI measurements for determining the microstructure of a mass of trabecular bone are described, for example, in A Review of Recent Advances in Magnetic Resonance Imaging in the Assessment of Osteoporosis, S. Majumdar. and H. K Genent, Osteoporosis International, Vol. 5, No. 2, pp. 79-92 (1995).
Nuclear Magnetic Resonance (NMR) methods in general are among the most useful nondestructive techniques of material analysis. Particularly, non-invasive examination of a human body by means of NMR is extensive. Specifically, MRI and Magnetic Resonance Spectroscopy (MRS) have many useful application in medical diagnostics. Although Quantitative Magnetic Resonance (QMR) has fewer applications when compared with MRI and MRS, QMR is increasingly being used as a diagnostic tool. In general, NMR/MRI instruments known in the art for analyzing bone typically make measurements corresponding to an amount of time for hydrogen nuclei present in the anatomical bone to substantially realign their spin axes, and consequently their bulk magnetization, with an applied static magnetic field. A superconducting electromagnet, conventional electromagnet or a permanent magnet typically provides the applied static magnetic field. The spin axes of hydrogen nuclei in the bone, in the aggregate, align with the static magnetic field applied by the magnet. Various sequences (selectable length and duration) of radio frequency (RF) magnetic fields are imparted to the bone to momentarily reorient the nuclear magnetic spins of the hydrogen nuclei. RF signals are generated by the hydrogen nuclei as they spin about their axes due to precession of the spin axes. The amplitude, duration and spatial distribution of these RF signals are related to properties of the material which are being investigated by the particular NMR techniques being used.
Conventional MRI can produce an image of the bone, but this image is typically only of the specific bone tissue surface because the number of free (not in chemically bound form) water molecules within the specific bone tissue, and consequently the number of free protons, is very small. It has proven impractical to image the internal structure of bone using MRI techniques known in the art. It is known in the art that bone contains small voids and blood vessels which do contain some free fluid. It is possible using MRI techniques known in the art to develop an image of the bone related to the fluid content of these small fluid-containing voids and vessels within the bone. A particular disadvantage of using conventional MRI techniques to develop such images within the bone, or of the surface of the bone, is the relatively long recovery time between measurements related to the relatively long relaxation time of free protons. It is desirable to be able to develop an image of the internal structure of the bone, and it is even more desirable to be able to develop such an image quickly.
U.S. Pat. No. 4,880,007 issued to Sadler et al and U.S. Pat. No. 5,593,659 issued to Winchell et al describe various methods of improving conventional MRI images using contrast improving agents. It is desirable to have a technique for imaging the internal structure of the bone without the use of such contrast improving agents, for reasons including potential toxicity of such agents, time for the agents to disperse in the body parts to be imaged, and the likelihood that the agent may not disperse sufficiently within the bone to properly image the internal structure thereof.
In the field of in-vivo analysis of bone there have been numerous attempts to use all of the above mentioned Magnetic Resonance methods and techniques. Briefly, these techniques and their limitations are as follows:
I. MRS (Magnetic Resonance Spectroscopy).
U.S. Pat. No. 4,635,643 issued to Brown discloses an MRS method to quantify mineral content of a bone by recording a .sup.31 P spectrum in vivo and comparing it to a MRS spectrum of a reference standard having known concentration of reference minerals. A drawback to this technique is the fact that many human tissue types contain a variety of phosphates which yield .sup.31 P peaks within a very narrow chemical shift range. Thus resolving an individual peak within a .sup.31 P MRS spectrum of measurements made on a bone is very difficult. In addition, MRS requires very high homogeneity and strength of the static magnetic field, due to the required high spectral resolution of chemical shifts, making MRS equipment extremely expensive.
II. MRI (Magnetic Resonance Imaging).
U.S. Pat. No. 5,247,934 issued to Wehrli et al. discloses an MRI method for osteoporosis diagnosis. The essence of the method in the '934 patent is to make an image of the microstructure of trabecular bone, and based on this image and certain empirical criteria, to calculate several trabecular bone parameters such as trabecular thickness, intercept length and fabric tensor. Then, by comparing the obtained set of parameters with data corresponding to a trabecular bone having a known condition, the condition of the bone being examined is then determined. Disadvantages of the method in the '934 patent are first, the typical MRI in-vivo images provide pixel sizes of about 0.5 to 1 millimeters (mm) and section thicknesses of about 2 to 3 mm. This resolution is insufficient to analyze trabecular bone microstructures, which would require image resolution less than the average trabecular thickness, which is about 100 micrometers (.mu.m). Images with a pixel size of 100.times.100.times.1000 micrometers, as described in the '934 patent, are about the smallest in-vivo pixel sizes which can be attained using the best currently available equipment. This resolution is still not sufficient to resolve trabecular bone microstructures. In addition there are fundamental limitations in MRI physics and technology as explained by Kuhn in, NMR Microscopy--Fundamentals, Limits and Possible Applications, ANGEWANDTE CHEMIE, International Edition in English, Vol. 29, No. 1, January 1990, pp. 1-19. The fundamental limitations may limit future improvements in spatial resolution of MRI measurement. Technological limitations include requirements for higher signal-to-noise ratio, more homogeneous and stable static magnetic field, and stronger and more linear magnetic field gradients. Physical limitations include the spectral signal line width and the effect of chemical shift on the measurement.
III. QMR (Quantitative Magnetic Resonance).
U.S. Pat. No. 5,270,651 issued to Wehrli discloses the use of the QMR method. This relaxometry-type method avoids the necessity for complicated and expensive equipment, but fails to overcome several limitations, such as trabecular bone being the only bone analyzed. As in the MRI method, fluids that occupy the intratrabecular spaces are not a simple type fluid, but include a mixture of blood, lipids, proteins and other fluids each having an individual NMR relaxation rate. Therefore, the NMR relaxation time spectrum may be extremely complicated, the relaxation time spectrum is also patient and skeletal site dependent, and the correlation between the relaxation time spectrum and the physical condition of bone, such as reduced BMD and consequent increase in risk of fractures (and more specifically osteoporotic conditions) is questionable. Internal magnetic field gradient distribution, which is the underlying phenomenon of this relaxometry QMR method, is not only a function of trabecular bone microstructure but also depends on the spatial distribution of the magnetic susceptibility of the materials being analyzed by NMR techniques. The assumption that the magnetic susceptibility of specific bone tissue and bone marrow is constant, as is required for this technique, is not highly accurate.
e. NMR techniques for analyzing materials other than human bone have been developed. These techniques, which are relevant to bone analysis, include the following:
NMR methods for quantitative analysis of moisture level or "solid" to "liquid" ratio are known in the art. Measuring fat content in margarine has become a very important application of such techniques. A more general approach is described, for example, in U.S. Pat. No. 5,539,309 issued to Van Wyk et al. which discloses a concept of "solid" to "liquid" ratio determination. Generally the technique works where there exist physically distinct phases having relaxation times which may be characterized as "fast" and "slow" relative to one another. This method is quite effective in cases when the relaxation times of the two phases are very different. The technique disclosed in the Van Wyk et al '309 patent, however, has low accuracy where the relaxation times are only marginally different, or when used for mixtures including several phases, such as for example, determining bound water content of fluid-bearing porous earth formations. Examples of similar applications includes: U.S. Pat. No. 5,818,228 issued to Menon et al. which discloses using a similar technique for measurement of the resin content of a composite material by NMR. U.S. Pat. No. 4,701,705 issued to Rollwitz which discloses a method for determining moisture of a material by determining the total hydrogen density of the material.
f. NMR technical issues relevant to NMR bone analysis include the following:
All of the previously described NMR techniques could be more effective if their signal-to-noise ratio could be improved significantly. This would lead to better precision, accuracy and spatial resolution irrespective of the selected NMR technique. This fact is recognized in an apparatus for noninvasive, localized, in-vivo examination of tissue, including bone, which is disclosed in U.S. Pat. No. 4,442,404 issued to Bergmann. The essence of the method and apparatus described in the Bergmann '404 patent is to use a detection coil maintained at superconducting temperature to achieve a high signal-to-noise ratio. This technique has not been used on a commercial basis due to engineering difficulties, and in many cases thermal noise is generated not only in the detection coil but also in the sample itself because the sample is electrically conductive.
Despite extensive research and development into methods of characterizing bone and the cause and treatment of osteoporosis, there is still a need for reliable, accurate, precise and specific non-invasive methods for acquiring information relating to the bone and for detecting, diagnosing and monitoring diseases such as osteoporosis.